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Development of Vaccines Based on Virus-Like Particles
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Development of Vaccines Based on Virus-Like Particles

A special issue of Vaccines (ISSN 2076-393X). This special issue belongs to the section "Vaccines against Infectious Diseases".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 52136

Special Issue Editors

Dr. Esther Blanco

E-Mail Website
Guest Editor
Center for Animal Health Research (CISA-INIA), Valdeolmos, 28130 Madrid, Spain
Interests: virology; vaccines; VLPs; peptides; calicivirus; picornavirus; T-epitopes; B-epitopes; adaptive immunity
Special Issues, Collections and Topics in MDPI journals
Dr. Juan Bárcena

E-Mail
Guest Editor
Center for Animal Health Research (CISA-INIA), Valdeolmos, 28130 Madrid, Spain
Interests: virology; vaccines; chimeric VLPs; caliciviruses
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Basic studies on virus structure and assembly have led to the experimental observation that many viral structural proteins have the intrinsic ability to self-assemble into virus-like particles (VLPs). These VLPs have led to better immunological mimics of whole-virus particles compared to soluble capsid subunits, resulting in the improved effectiveness of vaccines and leading to a renaissance in vaccine development.

VLP-based vaccines combine many of the advantages of whole-virus-based and recombinant subunit vaccines, exhibiting a high safety profile. VLPs produced using recombinant protein expression systems can stimulate strong B- and T-cell immune responses and have been shown to exhibit self-adjuvanting abilities. In addition, VLPs can be used as platforms for the multimeric display of foreign antigens of interest derived from viruses or other pathogens (chimeric VLPs).

This Special Issue aims to collect recent research work on the design, generation and use of VLPs and chimeric VLPs for the development of both human and veterinary new generation vaccines.

Dr. Esther Blanco
Dr. Juan Bárcena
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Vaccines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • virus-like particles
  • VLPs
  • chimeric VLPs
  • conjugated VLPs
  • virosomes
  • nanoparticles
  • nanocarriers
  • prophylactic vaccines
  • therapeutic vaccines
  • multimeric presentation
  • immune response

Related Special Issue

Published Papers (17 papers)

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16 pages, 2103 KiB  
Article
Vaccine Candidate Double Mutant Variants of Enterotoxigenic Escherichia coli Heat-Stable Toxin
by Ephrem Debebe Zegeye, Yuleima Diaz and Pål Puntervoll
Vaccines 2022, 10(2), 241; https://doi.org/10.3390/vaccines10020241 - 04 Feb 2022
Cited by 3 | Viewed by 1839
Abstract
Heat-stable enterotoxin (ST) producing enterotoxigenic Escherichia coli (ETEC) strains are among the top four enteropathogens associated with moderate-to-severe diarrhea in children under five years in low-to-middle income countries, thus making ST a target for an ETEC vaccine. However, ST must be mutated to [...] Read more.
Heat-stable enterotoxin (ST) producing enterotoxigenic Escherichia coli (ETEC) strains are among the top four enteropathogens associated with moderate-to-severe diarrhea in children under five years in low-to-middle income countries, thus making ST a target for an ETEC vaccine. However, ST must be mutated to abolish its enterotoxicity and to prevent a potential immunological cross-reaction due to its structural resemblance to the human peptides uroguanylin and guanylin. To reduce the risk of eliciting cross-reacting antibodies with our lead STh-A14T toxoid, L9 was chosen as an additional mutational target. A double mutant vaccine candidate immunogen, STh-L9A/A14T, was constructed by conjugation to the synthetic virus-like mi3 nanoparticle using the SpyTag/SpyCatcher technology. This immunogen elicited STh neutralizing antibodies in mice, but with less consistency than STh-A14T peptide control immunogens. Moreover, individual sera from mice immunized with both single and double mutant variants displayed varying levels of unwanted cross-reacting antibodies. The lowest levels of cross-reacting antibodies were observed with STh-L9K/A14T control immunogens, suggesting that it is indeed possible to reduce the risk of eliciting cross-reacting antibodies by mutation. However, mutant-specific antibodies were observed for most double mutant immunogens, demonstrating the delicate balancing act between disrupting cross-reacting epitopes, keeping protective ones, and avoiding the formation of neoepitopes. Full article
(This article belongs to the Special Issue Development of Vaccines Based on Virus-Like Particles)
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14 pages, 762 KiB  
Article
Immunogenicity and Protective Capacity of a Virus-like Particle Vaccine against Chlamydia trachomatis Type 3 Secretion System Tip Protein, CT584
by Everett Webster, Kyra W. Seiger, Susan B. Core, Amanda L. Collar, Hannah Knapp-Broas, June Graham, Muskan Shrestha, Sarah Afzaal, William M. Geisler, Cosette M. Wheeler, Bryce Chackerian, Kathryn M. Frietze and Rebeccah S. Lijek
Vaccines 2022, 10(1), 111; https://doi.org/10.3390/vaccines10010111 - 12 Jan 2022
Cited by 5 | Viewed by 2899
Abstract
An effective vaccine against Chlamydia trachomatis is urgently needed as infection rates continue to rise and C. trachomatis causes reproductive morbidity. An obligate intracellular pathogen, C. trachomatis employs a type 3 secretion system (T3SS) for host cell entry. The tip of the injectosome [...] Read more.
An effective vaccine against Chlamydia trachomatis is urgently needed as infection rates continue to rise and C. trachomatis causes reproductive morbidity. An obligate intracellular pathogen, C. trachomatis employs a type 3 secretion system (T3SS) for host cell entry. The tip of the injectosome is composed of the protein CT584, which represents a potential target for neutralization with vaccine-induced antibody. Here, we investigate the immunogenicity and efficacy of a vaccine made of CT584 epitopes coupled to a bacteriophage virus-like particle (VLP), a novel platform for Chlamydia vaccines modeled on the success of HPV vaccines. Female mice were immunized intramuscularly, challenged transcervically with C. trachomatis, and assessed for systemic and local antibody responses and bacterial burden in the upper genital tract. Immunization resulted in a 3-log increase in epitope-specific IgG in serum and uterine homogenates and in the detection of epitope-specific IgG in uterine lavage at low levels. By contrast, sera from women infected with C. trachomatis and virgin controls had similarly low titers to CT584 epitopes, suggesting these epitopes are not systemically immunogenic during natural infection but can be rendered immunogenic by the VLP platform. C. trachomatis burden in the upper genital tract of mice varied after active immunization, yet passive protection was achieved when immune sera were pre-incubated with C. trachomatis prior to inoculation into the genital tract. These data demonstrate the potential for antibody against the T3SS to contribute to protection against C. trachomatis and the value of VLPs as a novel platform for C. trachomatis vaccines. Full article
(This article belongs to the Special Issue Development of Vaccines Based on Virus-Like Particles)
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14 pages, 3894 KiB  
Article
A Comparative Study on Delivery of Externally Attached DNA by Papillomavirus VLPs and Pseudoviruses
by Sarah Brendle, Nancy Cladel, Karla Balogh, Samina Alam, Neil Christensen, Craig Meyers and Jiafen Hu
Vaccines 2021, 9(12), 1501; https://doi.org/10.3390/vaccines9121501 - 18 Dec 2021
Cited by 1 | Viewed by 2244
Abstract
Human papillomavirus (HPV) 16 capsids have been chosen as a DNA delivery vehicle in many studies. Our preliminary studies suggest that HPV58 capsids could be better vehicles than HPV16 capsids to deliver encapsidated DNA in vitro and in vivo. In the current study, [...] Read more.
Human papillomavirus (HPV) 16 capsids have been chosen as a DNA delivery vehicle in many studies. Our preliminary studies suggest that HPV58 capsids could be better vehicles than HPV16 capsids to deliver encapsidated DNA in vitro and in vivo. In the current study, we compared HPV16, HPV58, and the cottontail rabbit papillomavirus (CRPV) capsids either as L1/L2 VLPs or pseudoviruses (PSVs) to deliver externally attached GFP-expressing DNA. Both rabbit and human cells were used to test whether there was a species-specific effect. DNA delivery efficiency was determined by quantifying either GFP-expressing cell populations or mean fluorescent intensities (MFI) by flow cytometry. Interestingly, CRPV and 58-VLPs and PSVs were significantly more efficient at delivering attached DNA when compared to 16-VLPs and PSVs. A capsid/DNA ratio of 2:1 showed the highest efficiency for delivering external DNA. The PSVs with papillomavirus DNA genomes also showed higher efficiency than those with irrelevant plasmid DNA. HPV16L1/58L2 hybrid VLPs displayed increased efficiency compared to HPV58L1/16L2 VLPs, suggesting that L2 may play a critical role in the delivery of attached DNA. Additionally, we demonstrated that VLPs increased in vivo infectivity of CRPV DNA in rabbits. We conclude that choosing CRPV or 58 capsids to deliver external DNA could improve DNA uptake in in vitro and in vivo models. Full article
(This article belongs to the Special Issue Development of Vaccines Based on Virus-Like Particles)
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15 pages, 2845 KiB  
Article
Sublingual Immunization with Chimeric C1q/CD40 Ligand/HIV Virus-like Particles Induces Strong Mucosal Immune Responses against HIV
by Dongliang Liu, Sheng Zhang, Ethan Poteet, Christian Marin-Muller, Changyi Chen and Qizhi Yao
Vaccines 2021, 9(11), 1236; https://doi.org/10.3390/vaccines9111236 - 23 Oct 2021
Cited by 6 | Viewed by 1965
Abstract
Development of a vaccine that can elicit robust HIV specific antibody responses in the mucosal compartments is desired for effective prevention of HIV via sexual transmission. However, the current mucosal vaccines have either poor immunogenicity when administered orally or invite safety concerns when [...] Read more.
Development of a vaccine that can elicit robust HIV specific antibody responses in the mucosal compartments is desired for effective prevention of HIV via sexual transmission. However, the current mucosal vaccines have either poor immunogenicity when administered orally or invite safety concerns when administered intranasally. Sublingual immunization has received more attention in recent years based on its efficiency in inducing systemic and mucosal immune responses in both mucosal and extra-mucosal tissues. To facilitate the transport of the immunogen across the sub-mucosal epithelial barrier, we found that CD91, the receptor of C1q, is prevalently expressed in the sublingual mucosal lining, and thus, a modified chimeric C1q surface conjugated CD40L/HIV VLP was generated. The ability of this chimeric C1q/CD40L/HIV VLP to bind, cross the epithelial layer, access and activate the sub-mucosal layer dendritic cells (DCs), and ultimately induce enhanced mucosal and systemic immune responses against HIV is evaluated in this study. We found that C1q/CD40L/HIV VLPs have enhanced binding, increased transport across the epithelial layer, and upregulate DC activation markers as compared to CD40L/HIV VLPs alone. Mice immunized with C1q/CD40L/HIV VLPs by sublingual administration showed higher levels of IgA salivary antibodies against both HIV Gag and Env than mice immunized with CD40L/HIV VLPs. Moreover, sublingual immunization with C1q/CD40L/HIV VLPs induced more Env- and Gag-specific IFN-γ producing T cells than the CD40L/HIV VLPs group. Interestingly, C1q/CD40L/HIV VLP immunization can also induce more mucosal homing T cells than that in CD40L/HIV VLP group. Our data suggest that incorporation of C1q to CD40L/HIV VLPs is a promising novel strategy and that the sublingual immunization can be a favorite immunization route for HIV mucosal vaccines. Full article
(This article belongs to the Special Issue Development of Vaccines Based on Virus-Like Particles)
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19 pages, 4311 KiB  
Article
A Four-Step Purification Process for Gag VLPs: From Culture Supernatant to High-Purity Lyophilized Particles
by Irene González-Domínguez, Elianet Lorenzo, Alice Bernier, Laura Cervera, Francesc Gòdia and Amine Kamen
Vaccines 2021, 9(10), 1154; https://doi.org/10.3390/vaccines9101154 - 09 Oct 2021
Cited by 9 | Viewed by 2835
Abstract
Gag-based virus-like particles (VLPs) have high potential as scaffolds for the development of chimeric vaccines and delivery strategies. The production of purified preparations that can be preserved independently from cold chains is highly desirable to facilitate distribution and access worldwide. In this work, [...] Read more.
Gag-based virus-like particles (VLPs) have high potential as scaffolds for the development of chimeric vaccines and delivery strategies. The production of purified preparations that can be preserved independently from cold chains is highly desirable to facilitate distribution and access worldwide. In this work, a nimble purification has been developed, facilitating the production of Gag VLPs. Suspension-adapted HEK 293 cells cultured in chemically defined cell culture media were used to produce the VLPs. A four-step downstream process (DSP) consisting of membrane filtration, ion-exchange chromatography, polishing, and lyophilization was developed. The purification of VLPs from other contaminants such as host cell proteins (HCP), double-stranded DNA, or extracellular vesicles (EVs) was confirmed after their DSP. A concentration of 2.2 ± 0.8 × 109 VLPs/mL in the lyophilized samples was obtained after its storage at room temperature for two months. Morphology and structural integrity of purified VLPs was assessed by cryo-TEM and NTA. Likewise, the purification methodologies proposed here could be easily scaled up and applied to purify similar enveloped viruses and vesicles. Full article
(This article belongs to the Special Issue Development of Vaccines Based on Virus-Like Particles)
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16 pages, 1674 KiB  
Article
Chimeric VLPs Bearing VP60 from Two Serotypes of Rabbit Haemorrhagic Disease Virus Are Protective against Both Viruses
by Kevin P. Dalton, Carmen Alvarado, Edel Reytor, Maria del Carmen Nuñez, Ana Podadera, Diego Martínez-Alonso, Jose Manuel Martin Alonso, Ines Nicieza, Silvia Gómez-Sebastián, Romy M. Dalton, Francisco Parra and José M. Escribano
Vaccines 2021, 9(9), 1005; https://doi.org/10.3390/vaccines9091005 - 09 Sep 2021
Cited by 6 | Viewed by 2402
Abstract
The VP60 capsid protein from rabbit haemorrhagic disease virus (RHDV), the causative agent of one of the most economically important disease in rabbits worldwide, forms virus-like particles (VLPs) when expressed using heterologous protein expression systems such as recombinant baculovirus, yeasts, plants or mammalian [...] Read more.
The VP60 capsid protein from rabbit haemorrhagic disease virus (RHDV), the causative agent of one of the most economically important disease in rabbits worldwide, forms virus-like particles (VLPs) when expressed using heterologous protein expression systems such as recombinant baculovirus, yeasts, plants or mammalian cell cultures. To prevent RHDV dissemination, it would be beneficial to develop a bivalent vaccine including both RHDV GI.1- and RHDV GI.2-derived VLPs to achieve robust immunisation against both serotypes. In the present work, we developed a strategy of production of a dual-serving RHDV vaccine co-expressing the VP60 proteins from the two RHDV predominant serotypes using CrisBio technology, which uses Tricholusia ni insect pupae as natural bioreactors, which are programmed by recombinant baculovirus vectors. Co-infecting the insect pupae with two baculovirus vectors expressing the RHDV GI.1- and RHDV GI.2-derived VP60 proteins, we obtained chimeric VLPs incorporating both proteins as determined by using serotype-specific monoclonal antibodies. The resulting VLPs showed the typical size and shape of this calicivirus as determined by electron microscopy. Rabbits immunised with the chimeric VLPs were fully protected against a lethal challenge infection with the two RHDV serotypes. This study demonstrates that it is possible to generate a dual cost-effective vaccine against this virus using a single production and purification process, greatly simplifying vaccine manufacturing. Full article
(This article belongs to the Special Issue Development of Vaccines Based on Virus-Like Particles)
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13 pages, 2990 KiB  
Article
Development of Bacteriophage Virus-Like Particle Vaccines Displaying Conserved Epitopes of Dengue Virus Non-Structural Protein 1
by Nikole L. Warner and Kathryn M. Frietze
Vaccines 2021, 9(7), 726; https://doi.org/10.3390/vaccines9070726 - 02 Jul 2021
Cited by 10 | Viewed by 2994
Abstract
Dengue virus (DENV) is a major global health problem, with over half of the world’s population at risk of infection. Despite over 60 years of efforts, no licensed vaccine suitable for population-based immunization against DENV is available. Here, we describe efforts to engineer [...] Read more.
Dengue virus (DENV) is a major global health problem, with over half of the world’s population at risk of infection. Despite over 60 years of efforts, no licensed vaccine suitable for population-based immunization against DENV is available. Here, we describe efforts to engineer epitope-based vaccines against DENV non-structural protein 1 (NS1). NS1 is present in DENV-infected cells as well as secreted into the blood of infected individuals. NS1 causes disruption of endothelial cell barriers, resulting in plasma leakage and hemorrhage. Immunizing against NS1 could elicit antibodies that block NS1 function and also target NS1-infected cells for antibody-dependent cell cytotoxicity. We identified highly conserved regions of NS1 from all four DENV serotypes. We generated synthetic peptides to these regions and chemically conjugated them to bacteriophage Qβ virus-like particles (VLPs). Mice were immunized two times with the candidate vaccines and sera were tested for the presence of antibodies that bound to the cognate peptide, recombinant NS1 from all four DENV serotypes, and DENV-2-infected cells. We found that two of the candidate vaccines elicited antibodies that bound to recombinant NS1, and one candidate vaccine elicited antibodies that bound to DENV-infected cells. These results show that an epitope-specific vaccine against conserved regions of NS1 could be a promising approach for DENV vaccines or therapeutics to bind circulating NS1 protein. Full article
(This article belongs to the Special Issue Development of Vaccines Based on Virus-Like Particles)
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11 pages, 1917 KiB  
Article
Head-to-Head Comparison of Modular Vaccines Developed Using Different Capsid Virus-Like Particle Backbones and Antigen Conjugation Systems
by Laurits Fredsgaard, Louise Goksøyr, Susan Thrane, Kara-Lee Aves, Thor G. Theander and Adam F. Sander
Vaccines 2021, 9(6), 539; https://doi.org/10.3390/vaccines9060539 - 21 May 2021
Cited by 6 | Viewed by 3304
Abstract
Capsid virus-like particles (cVLPs) are used as molecular scaffolds to increase the immunogenicity of displayed antigens. Modular platforms have been developed whereby antigens are attached to the surface of pre-assembled cVLPs. However, it remains unknown to what extent the employed cVLP backbone and [...] Read more.
Capsid virus-like particles (cVLPs) are used as molecular scaffolds to increase the immunogenicity of displayed antigens. Modular platforms have been developed whereby antigens are attached to the surface of pre-assembled cVLPs. However, it remains unknown to what extent the employed cVLP backbone and conjugation system may influence the immune response elicited against the displayed antigen. Here, we performed a head-to-head comparison of antigen-specific IgG responses elicited by modular cVLP-vaccines differing by their employed cVLP backbone or conjugation system, respectively. Covalent antigen conjugation (i.e., employing the SpyTag/SpyCatcher system) resulted in significantly higher antigen-specific IgG titers compared to when using affinity-based conjugation (i.e., using biotin/streptavidin). The cVLP backbone also influenced the antigen-specific IgG response. Specifically, vaccines based on the bacteriophage AP205 cVLP elicited significantly higher antigen-specific IgG compared to corresponding vaccines using the human papillomavirus major capsid protein (HPV L1) cVLP. In addition, the AP205 cVLP platform mediated induction of antigen-specific IgG with a different subclass profile (i.e., higher IgG2a and IgG2b) compared to HPV L1 cVLP. These results demonstrate that the cVLP backbone and conjugation system can individually affect the IgG response elicited against a displayed antigen. These data will aid the understanding and process of tailoring modular cVLP vaccines to achieve improved immune responses. Full article
(This article belongs to the Special Issue Development of Vaccines Based on Virus-Like Particles)
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22 pages, 3211 KiB  
Article
Chimeric RHDV Virus-Like Particles Displaying Foot-and-Mouth Disease Virus Epitopes Elicit Neutralizing Antibodies and Confer Partial Protection in Pigs
by Giselle Rangel, Juan Bárcena, Noelia Moreno, Carlos P. Mata, José R. Castón, Alí Alejo and Esther Blanco
Vaccines 2021, 9(5), 470; https://doi.org/10.3390/vaccines9050470 - 07 May 2021
Cited by 5 | Viewed by 3080
Abstract
Currently there is a clear trend towards the establishment of virus-like particles (VLPs) as a powerful tool for vaccine development. VLPs are tunable nanoparticles that can be engineered to be used as platforms for multimeric display of foreign antigens. We have previously reported [...] Read more.
Currently there is a clear trend towards the establishment of virus-like particles (VLPs) as a powerful tool for vaccine development. VLPs are tunable nanoparticles that can be engineered to be used as platforms for multimeric display of foreign antigens. We have previously reported that VLPs derived from rabbit hemorrhagic disease virus (RHDV) constitute an excellent vaccine vector, capable of inducing specific protective immune responses against inserted heterologous T-cytotoxic and B-cell epitopes. Here, we evaluate the ability of chimeric RHDV VLPs to elicit immune response and protection against Foot-and-Mouth disease virus (FMDV), one of the most devastating livestock diseases. For this purpose, we generated a set of chimeric VLPs containing two FMDV-derived epitopes: a neutralizing B-cell epitope (VP1 (140–158)) and a T-cell epitope [3A (21–35)]. The epitopes were inserted joined or individually at two different locations within the RHDV capsid protein. The immunogenicity and protection potential of the chimeric VLPs were analyzed in the mouse and pig models. Herein we show that the RHDV engineered VLPs displaying FMDV-derived epitopes elicit a robust neutralizing immune response in mice and pigs, affording partial clinical protection against an FMDV challenge in pigs. Full article
(This article belongs to the Special Issue Development of Vaccines Based on Virus-Like Particles)
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14 pages, 11481 KiB  
Article
Delivering Two Tumour Antigens Survivin and Mucin-1 on Virus-Like Particles Enhances Anti-Tumour Immune Responses
by Katrin Campbell, Vivienne L. Young, Braeden C. Donaldson, Matthew J. Woodall, Nicholas J. Shields, Greg F. Walker, Vernon K. Ward and Sarah L. Young
Vaccines 2021, 9(5), 463; https://doi.org/10.3390/vaccines9050463 - 06 May 2021
Cited by 15 | Viewed by 3178
Abstract
Breast cancer (BC) is the most frequently diagnosed cancer in women, with many patients experiencing recurrence following treatment. Antigens delivered on virus-like particles (VLPs) induce a targeted immune response and here we investigated whether the co-delivery of multiple antigens could induce a superior [...] Read more.
Breast cancer (BC) is the most frequently diagnosed cancer in women, with many patients experiencing recurrence following treatment. Antigens delivered on virus-like particles (VLPs) induce a targeted immune response and here we investigated whether the co-delivery of multiple antigens could induce a superior anti-cancer response for BC immunotherapy. VLPs were designed to recombinantly express murine survivin and conjugated with an aberrantly glycosylated mucin-1 (MUC1) peptide using an intracellular cleavable bis-arylhydrazone linker. Western blotting, electron microscopy and UV absorption confirmed survivin-VLP expression and MUC1 conjugation. To assess the therapeutic efficacy of VLPs, orthotopic BC tumours were established by injecting C57mg.MUC1 cells into the mammary fat pad of mice, which were then vaccinated with surv.VLP-SS-MUC1 or VLP controls. While wild-type mice vaccinated with surv.VLP-SS-MUC1 showed enhanced survival compared to VLPs delivering either antigen alone, MUC1 transgenic mice vaccinated with surv.VLP-SS-MUC1 showed no enhanced survival compared to controls. Hence, while co-delivery of two tumour antigens on VLPs can induce a superior anti-tumour immune response compared to the delivery of single antigens, additional strategies must be employed to break tolerance when targeted tumour antigens are expressed as endogenous self-proteins. Using VLPs for the delivery of multiple antigens represents a promising approach to improving BC immunotherapy, and has the potential to be an integral part of combination therapy in the future. Full article
(This article belongs to the Special Issue Development of Vaccines Based on Virus-Like Particles)
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22 pages, 6698 KiB  
Article
Long-Term Protection and Serologic Response of European Sea Bass Vaccinated with a Betanodavirus Virus-Like Particle Produced in Pichia pastoris
by Sofie Barsøe, Anna Toffan, Francesco Pascoli, Ansgar Stratmann, Tobia Pretto, Andrea Marsella, Mériem Er-Rafik, Niccolò Vendramin, Niels J. Olesen, Dagoberto Sepúlveda and Niels Lorenzen
Vaccines 2021, 9(5), 447; https://doi.org/10.3390/vaccines9050447 - 02 May 2021
Cited by 8 | Viewed by 3295
Abstract
Viral Nervous Necrosis (VNN) causes high mortality and reduced growth in farmed European sea bass (Dicentrarchus labrax) in the Mediterranean. In the current studies, we tested a novel Pichia-produced virus-like particle (VLP) vaccine against VNN in European sea bass, caused [...] Read more.
Viral Nervous Necrosis (VNN) causes high mortality and reduced growth in farmed European sea bass (Dicentrarchus labrax) in the Mediterranean. In the current studies, we tested a novel Pichia-produced virus-like particle (VLP) vaccine against VNN in European sea bass, caused by the betanodavirus “Red-Spotted Grouper Nervous Necrosis Virus” (RGNNV). European sea bass were immunized with a VLP-based vaccine formulated with different concentrations of antigen and with or without adjuvant. Antibody response was evaluated by ELISA and serum neutralization. The efficacy of these VLP-vaccine formulations was evaluated by an intramuscular challenge with RGNNV at different time points (1, 2 and 10 months post-vaccination) and both dead and surviving fish were sampled to evaluate the level of viable virus in the brain. The VLP-based vaccines induced an effective protective immunity against experimental infection at 2 months post-vaccination, and even to some degree at 10 months post-vaccination. Furthermore, the vaccine formulations triggered a dose-dependent response in neutralizing antibodies. Serologic response and clinical efficacy, measured as relative percent survival (RPS), seem to be correlated with the administered dose, although for the individual fish, a high titer of neutralizing antibodies prior to challenge was not always enough to protect against disease. The efficacy of the VLP vaccine could not be improved by formulation with a water-in-oil (W/O) adjuvant. The developed RGNNV-VLPs show a promising effect as a vaccine candidate, even without adjuvant, to protect sea bass against disease caused by RGNNV. However, detection of virus in vaccinated survivors means that it cannot be ruled out that survivors can transmit the virus. Full article
(This article belongs to the Special Issue Development of Vaccines Based on Virus-Like Particles)
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14 pages, 607 KiB  
Article
Differential Antibody Response against Conformational and Linear Epitopes of the L1 Proteins from Human Papillomavirus Types 16/18 Is Observed in Vaccinated Women or with Uterine Cervical Lesions
by Adolfo Pedroza-Saavedra, Angelica Nallelhy Rodriguez-Ocampo, Azucena Salazar-Piña, Aislinn Citlali Perez-Morales, Lilia Chihu-Amparan, Minerva Maldonado-Gama, Aurelio Cruz-Valdez, Fernando Esquivel-Guadarrama and Lourdes Gutierrez-Xicotencatl
Vaccines 2021, 9(5), 442; https://doi.org/10.3390/vaccines9050442 - 02 May 2021
Viewed by 2270
Abstract
Antibodies against the Human Papillomavirus (HPV) L1 protein are associated with past infections and related to the evolution of the disease, whereas antibodies against L1 Virus-Like Particles (VLPs) are used to follow the neutralizing antibody response in vaccinated women. In this study, serum [...] Read more.
Antibodies against the Human Papillomavirus (HPV) L1 protein are associated with past infections and related to the evolution of the disease, whereas antibodies against L1 Virus-Like Particles (VLPs) are used to follow the neutralizing antibody response in vaccinated women. In this study, serum antibodies against conformational (VLPs) and linear epitopes of HPV16/18 L1 protein were assessed to distinguish HPV-vaccinated women from those naturally infected or those with uterine cervical lesions. The VLPs-16/18 were generated in baculovirus, and L1 proteins were obtained from denatured VLPs. Serum antibodies against VLPs and L1 proteins were evaluated by ELISA. The ELISA-VLPs and ELISA-L1 16/18 assays were validated with a vaccinated women group by ROC analysis and the regression analysis to distinguish the different populations of female patients. The anti-VLPs-16/18 and anti-L1-16/18 antibodies effectively detect vaccinated women (AUC = 1.0/0.79, and 0.94/0.84, respectively). The regression analysis showed that anti-VLPs-16/18 and anti-L1-16/18 antibodies were associated with the vaccinated group (OR = 2.11 × 108/16.50 and 536.0/49.2, respectively). However, only the anti-L1-16 antibodies were associated with the high-grade lesions and cervical cancer (CIN3/CC) group (OR = 12.18). In conclusion, our results suggest that anti-VLPs-16/18 antibodies are effective and type-specific to detect HPV-vaccinated women, but anti-L1-16 antibodies better differentiate the CIN3/CC group. However, a larger population study is needed to validate these results. Full article
(This article belongs to the Special Issue Development of Vaccines Based on Virus-Like Particles)
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17 pages, 4685 KiB  
Article
Chimeric VLPs Based on HIV-1 Gag and a Fusion Rabies Glycoprotein Induce Specific Antibodies against Rabies and Foot-and-Mouth Disease Virus
by Diego Fontana, Ernesto Garay, Laura Cervera, Ricardo Kratje, Claudio Prieto and Francesc Gòdia
Vaccines 2021, 9(3), 251; https://doi.org/10.3390/vaccines9030251 - 12 Mar 2021
Cited by 15 | Viewed by 3136
Abstract
Foot and mouth disease is a livestock acute disease, causing economic losses in affected areas. Currently, control of this disease is performed by mandatory vaccination campaigns using inactivated viral vaccines. In this work, we describe the development of a chimeric VLP-based vaccine candidate [...] Read more.
Foot and mouth disease is a livestock acute disease, causing economic losses in affected areas. Currently, control of this disease is performed by mandatory vaccination campaigns using inactivated viral vaccines. In this work, we describe the development of a chimeric VLP-based vaccine candidate for foot-and-mouth disease virus (FMDV), based on the co-expression of the HIV-1 Gag protein and a novel fusion rabies glycoprotein (RVG), which carries in its N-term the FMDV main antigen: the G-H loop. It is demonstrated by confocal microscopy that both Gag-GFP polyprotein and the G-H loop colocalize at the cell membrane and, that the Gag polyprotein of the HIV virus acts as a scaffold for enveloped VLPs that during the budding process acquires the proteins that are being expressed in the cell membrane. The obtained VLPs were spherical particles of 130 ± 40 nm in diameter (analyzed by TEM, Cryo-TEM and NTA) carrying an envelope membrane that efficiently display the GH-RVG on its surface (analyzed by gold immunolabeling). Immunostainings with a FMDV hyperimmune serum showed that the heterologous antigenic site, genetically fused to RVG, is recognized by specific G-H loop antibodies. Additionally, the cVLPs produced expose the G-H loop to the liquid surrounding (analyzed by specific ELISA). Finally, we confirmed that these FMD cVLPs are able to induce a specific humoral immune response, based on antibodies directed to the G-H loop in experimental animals. Full article
(This article belongs to the Special Issue Development of Vaccines Based on Virus-Like Particles)
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13 pages, 2259 KiB  
Article
Dry Formulation of Virus-Like Particles in Electrospun Nanofibers
by Sasheen Dowlath, Katrin Campbell, Farah Al-Barwani, Vivienne L. Young, Sarah L. Young, Greg F. Walker and Vernon K. Ward
Vaccines 2021, 9(3), 213; https://doi.org/10.3390/vaccines9030213 - 03 Mar 2021
Cited by 5 | Viewed by 2804
Abstract
Biologics can be combined with liquid polymer materials and electrospun to produce a dry nanofibrous scaffold. Unlike spray-drying and freeze-drying, electrospinning minimizes the physiological stress on sensitive materials, and nanofiber mat properties such as hydrophobicity, solubility, and melting temperature can be tuned based [...] Read more.
Biologics can be combined with liquid polymer materials and electrospun to produce a dry nanofibrous scaffold. Unlike spray-drying and freeze-drying, electrospinning minimizes the physiological stress on sensitive materials, and nanofiber mat properties such as hydrophobicity, solubility, and melting temperature can be tuned based on the polymer composition. In this study, we explored the dry formulation of a virus-like particle (VLP) vaccine by electrospinning VLP derived from rabbit hemorrhagic disease virus modified to carry the MHC-I gp100 tumor-associated antigen epitope. VLP were added to a polyvinylpyrrolidone (PVP) solution (15% w/v) followed by electrospinning at 24 kV. Formation of a nanofibrous mat was confirmed by scanning electron microscopy, and the presence of VLP was confirmed by transmission electron microscopy and Western blot. VLP from the nanofibers induced T-cell activation and interferon- (IFN-) γ production in vitro. To confirm in vivo cytotoxicity, Pmel mice treated by injection with gp100 VLP from nanofibers induced a gp100 specific immune response, lysing approximately 65% of gp100-pulsed target cells, comparable to mice vaccinated with gp100 VLP in PBS. VLP from nanofibers also induced an antibody response. This work shows that electrospinning can be used to dry-formulate VLP, preserving both humoral and cell-mediated immunity. Full article
(This article belongs to the Special Issue Development of Vaccines Based on Virus-Like Particles)
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Graphical abstract

14 pages, 1247 KiB  
Article
The Immunogenicity of Capsid-Like Particle Vaccines in Combination with Different Adjuvants Using Different Routes of Administration
by Christoph M. Janitzek, Philip H. R. Carlsen, Susan Thrane, Vijansh M. Khanna, Virginie Jakob, Christophe Barnier-Quer, Nicolas Collin, Thor G. Theander, Ali Salanti, Morten A. Nielsen and Adam F. Sander
Vaccines 2021, 9(2), 131; https://doi.org/10.3390/vaccines9020131 - 06 Feb 2021
Cited by 4 | Viewed by 3583
Abstract
Capsid-like particle (CLP) displays can be used to enhance the immunogenicity of vaccine antigens, but a better understanding of how CLP vaccines are best formulated and delivered is needed. This study compared the humoral immune responses in mice elicited against two different vaccine [...] Read more.
Capsid-like particle (CLP) displays can be used to enhance the immunogenicity of vaccine antigens, but a better understanding of how CLP vaccines are best formulated and delivered is needed. This study compared the humoral immune responses in mice elicited against two different vaccine antigens (a bacterial protein and a viral peptide) delivered on an AP205 CLP platform using six different adjuvant formulations. In comparison to antibody responses obtained after immunization with the unadjuvanted CLP vaccine, three of the adjuvant systems (neutral liposomes/monophosphoryl lipid A/quillaja saponaria 21, squalene-in-water emulsion, and monophosphoryl lipid A) caused significantly increased antibody levels, whereas formulation with the three other adjuvants (aluminum hydroxide, cationic liposomes, and cationic microparticles) resulted in similar or even decreased antibody responses. When delivering the soluble bacterial protein in a squalene-in-water emulsion, 4-log lower IgG levels were obtained compared to when the protein was delivered on CLPs without the adjuvant. The AP205 CLP platform promoted induction of both IgG1 and IgG2 subclasses, which could be skewed towards a higher production of IgG1 (aluminum hydroxide). Compared to other routes, intramuscular administration elicited the highest IgG levels. These results indicate that the effect of the external adjuvant does not always synergize with the adjuvant effect of the CLP display, which underscores the need for empirical testing of different extrinsic adjuvants. Full article
(This article belongs to the Special Issue Development of Vaccines Based on Virus-Like Particles)
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14 pages, 2503 KiB  
Article
Modulation of Antigen Display on PapMV Nanoparticles Influences Its Immunogenicity
by Marie-Eve Laliberté-Gagné, Marilène Bolduc, Caroline Garneau, Santa-Mariela Olivera-Ugarte, Pierre Savard and Denis Leclerc
Vaccines 2021, 9(1), 33; https://doi.org/10.3390/vaccines9010033 - 08 Jan 2021
Cited by 5 | Viewed by 2248
Abstract
Background: The papaya mosaic virus (PapMV) vaccine platform is a rod-shaped nanoparticle made of the recombinant PapMV coat protein (CP) self-assembled around a noncoding single-stranded RNA (ssRNA) template. The PapMV nanoparticle induces innate immunity through stimulation of the Toll-like receptors (TLR) 7 and [...] Read more.
Background: The papaya mosaic virus (PapMV) vaccine platform is a rod-shaped nanoparticle made of the recombinant PapMV coat protein (CP) self-assembled around a noncoding single-stranded RNA (ssRNA) template. The PapMV nanoparticle induces innate immunity through stimulation of the Toll-like receptors (TLR) 7 and 8. The display of the vaccine antigen at the surface of the nanoparticle, associated with the co-stimulation signal via TLR7/8, ensures a strong stimulation of the immune response, which is ideal for the development of candidate vaccines. In this study, we assess the impact of where the peptide antigen is fused, whether at the surface or at the extremities of the nanoparticles, on the immune response directed to that antigen. Methods: Two different peptides from influenza A virus were used as model antigens. The conserved M2e peptide, derived from the matrix protein 2 was chosen as the B-cell epitope, and a peptide derived from the nucleocapsid was chosen as the cytotoxic T lymphocytes (CTL) epitope. These peptides were coupled at two different positions on the PapMV CP, the N- (PapMV-N) or the C-terminus (PapMV-C), using the transpeptidase activity of Sortase A (SrtA). The immune responses, both humoral and CD8+ T-cell-mediated, directed to the peptide antigens in the two different fusion contexts were analyzed and compared. The impact of coupling density at the surface of the nanoparticle was also investigated. Conclusions: The results demonstrate that coupling of the peptide antigens at the N-terminus (PapMV-N) of the PapMV CP led to an enhanced immune response to the coupled peptide antigens as compared to coupling to the C-terminus. The difference between the two vaccine platforms is linked to the enhanced capacity of the PapMV-N vaccine platform to stimulate TLR7/8. We also demonstrated that the strength of the immune response increases with the density of coupling at the surface of the nanoparticles. Full article
(This article belongs to the Special Issue Development of Vaccines Based on Virus-Like Particles)
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Review

Jump to: Research

24 pages, 1087 KiB  
Review
Virus-like Particle Vaccines: A Prospective Panacea Against an Avian Influenza Panzootic
by Nathaniel Nyakaat Ninyio, Kok Lian Ho, Abdul Rahman Omar, Wen Siang Tan, Munir Iqbal and Abdul Razak Mariatulqabtiah
Vaccines 2020, 8(4), 694; https://doi.org/10.3390/vaccines8040694 - 19 Nov 2020
Cited by 11 | Viewed by 6289
Abstract
Epizootics of highly pathogenic avian influenza (HPAI) have resulted in the deaths of millions of birds leading to huge financial losses to the poultry industry worldwide. The roles of migratory wild birds in the harbouring, mutation, and transmission of avian influenza viruses (AIVs), [...] Read more.
Epizootics of highly pathogenic avian influenza (HPAI) have resulted in the deaths of millions of birds leading to huge financial losses to the poultry industry worldwide. The roles of migratory wild birds in the harbouring, mutation, and transmission of avian influenza viruses (AIVs), and the lack of broad-spectrum prophylactic vaccines present imminent threats of a global panzootic. To prevent this, control measures that include effective AIV surveillance programmes, treatment regimens, and universal vaccines are being developed and analysed for their effectiveness. We reviewed the epidemiology of AIVs with regards to past avian influenza (AI) outbreaks in birds. The AIV surveillance programmes in wild and domestic birds, as well as their roles in AI control were also evaluated. We discussed the limitations of the currently used AI vaccines, which necessitated the development of a universal vaccine. We evaluated the current development of AI vaccines based upon virus-like particles (VLPs), particularly those displaying the matrix-2 ectodomain (M2e) peptide. Finally, we highlighted the prospects of these VLP vaccines as universal vaccines with the potential of preventing an AI panzootic. Full article
(This article belongs to the Special Issue Development of Vaccines Based on Virus-Like Particles)
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